[Sperm mitochondrial DNA and male infertility: An update].

Sperm mitochondrial DNA (mtDNA) damage is closely related with male infertility. Lacking for the protection by histone and DNA-binding protein, sperm mtDNA is prone to the attack by reactive oxygen species (ROS) and, without an effective repair system of mtDNA, ROS-induced changes in mtDNA may damage the synthesis of mtDNA encoding proteins and affect the function of mitochondria, which may be an important genetic factor for male infertility. Related studies should focus on finding the causes of sperm mtDNA damage and its relationship with male infertility.

Evaluation of association between methylenetetrahydrofolate reductase and azoospermia: A meta-analysis.

BACKGROUND: Infertility affects childbearing age couples all over the world. One of the important reasons for infertility is genetic factors. Our study evaluated the association between methylenetetrahydrofolate reductase (MTHFR) and azoospermia. METHODS: Multiple databases like MEDLINE, EMBASE, Cochrane library, and China journal full-text database were used to search for relevant studies, and full-text articles involved in the evaluation of MTHFR and azoospermia. The results were evaluated using STATA 12.0. Heterogeneity analysis, sensitivity analysis, and bias analysis were also performed on the data. RESULTS: Thirteen related studies eventually met the inclusion criteria. Significant association between C677T polymorphism and azoospermia (relative risk [RR] = 0.94 [0.90, 0.99], I2 = 60.9%, P = .002), and between A1298C polymorphism and azoospermia (RR = 0.98 [0.94, 1.02], I2 = 56.3%, P = .011) was observed. Meanwhile, in subgroup analysis, Caucasians had higher risk than Mongolians in association between MTHFR and azoospermia. CONCLUSION: There was association between MTHFR polymorphism and azoospermia. Caucasian populations had higher risk than Mongolian populations in association between MTHFR and azoospermia.

Gefitinib analogue V1801 induces apoptosis of T790M EGFR-harboring lung cancer cells by up-regulation of the BH-3 only protein Noxa.

Treatment of non-small cell lung cancer (NSCLC) with drugs targeting the epidermal growth factor receptor (EGFR), e.g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategies to overcome this resistance are therefore an urgent need. In this study, we synthesized a dozen of novel gefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-bromo-5-(trifluoromethyl) phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine (hereafter, V1801), triggered apoptosis of the NSCLC cells and overcame gefitinib-resistance in mice inoculated with NCI-H1975 cells. Though V1801 only moderately inhibited EGFR kinase activity, it markedly induced the expression of the BH3-only protein Noxa, and Noxa silencing significantly reduced V1801-induced apoptosis of NCI-H1975 cells. It is showed that V1801 interfered with the expression of the transcription factor c-Myc and the extracellular signal regulated kinase (Erk) pathway. V1801 in combination with proteasome inhibitor bortezomib exerted enhanced cytotoxicity in NCI-H1975 cells possibly due to potentiated induction of Noxa expression. These data indicate that gefinitib analogues with weak EGFR inhibitory activity may overcome drug-resistance via activation of BH-3 only pro-apoptotic proteins, and V1801 may have therapeutic potentials for NSCLC.

Tuning the acyclic ether moiety of anticancer agent AA005 with conformationally constrained fragments.

A new series of anticancer annonaceous acetogenin mimetics were designed, synthesized, and evaluated based on our previously developed compound AA005, in which a variety of conformationally constrained fragments were introduced. Parallel syntheses of all new compounds were accomplished by replacement of the acyclic bis-ether functionality of AA005 with certain conformationally constrained fragments. Slight effects to the anticancer activity were exerted by altering stereochemistries in the middle modification region. Similar to AA005, most newly synthesized mimetics were found to exhibit potent activities against breast cancer cells, and showed satisfactory selectivities between cancerous and non-cancerous cells. An N,N'-dimethyl bis-amide compound 67 exhibits 30 times more potency against MDA-MB-468 cells than its parent molecule AA005. This study indicates that the introduction of appropriate conformational constraints is a useful optimizing tool for this class of anticancer agents. Successes in the bis-amide analogues of AA005 make this unique class of anticancer agents much simpler and more flexible for future further developments.